Ether compound as inhalation anesthetics

ABSTRACT

Aliphatic ether compounds of the formula CHF2 - CH2 - O - CF2 - CHX2 wherein each X is F or Cl, are useful as inhalation anesthetics.

United States Patent UNITED STATES PATENTS 12/1969 Krantz et a1. 424/342Terrell Jan. 21, 1975 ETHER COMPOUND AS INHALATION 3.557.294 1/1971 Dearet a] 260/614 F ANESTHETICS OTHER PUBLICATIONS T ll, 1 [75] InventorRess C erre P amfield N J y et JACS 65334536 1957. [73] Asslgnee: All-c0New York Larsen, Fluorine Chemistry Reviews 3 p. I, 38-39, [22] Filed:Mar. 19, 1973 1969.

[21] Appl. No.: 342,900

Prtmary ExaminerHoward T. Mars Related Application Data Attorney, Agent,or Firm-Roger M. Rathbun;

[62] Division of Ser. No. 174,248, Aug. 23, 1971, Pat. No. Edmund W.Bopp; H. Hume Mathews 52 U.S. c1. 260/614 F [57] ABSTRACT I [51] Int.Cl. C07C 43/00 Aliphatic ether compounds of the formula [58] Field ofSearch 260/614 F H]: CH2 Q 3 CHX2 .fls'hlt' References Citedgsl'tlfigiilgstfach X is F or C are use u as 1n :1 a lOl'l an 4 Claims,N0 Drawings ETHER COMPOUND AS INHALATION ANESTHETICS This application isa divisional application of US. Pat. application Ser. No. 174,248, filedAug. 23, 1971, now U.S. Pat. No. 3,746,769.

This invention relates to certain aliphatic ether compounds and theiruse in producing anesthesia in anesthetic-susceptible mammals.

The compounds of the present invention have the formula Cl-IF CH CF CHXwherein each X is F or Cl. These compounds lend themselves to effectiveuse as inhalant anesthetics in respirable mixtures containinglife-supporting concentrations of oxygen, with or without otherinhalation anesthetics, such as nitrous oxide. Administration of thecompounds may be any of the well known techniques for administeringgeneral inhalation anesthetics, for example by using the open drip,semi-closed or closed systems.

The effective amounts of the compounds of this invention to be employeddepend on the level of anesthesia to which the mammal is to be brought,the rate at which anesthesia is to be induced, and the length of timeover which anesthesia is to be maintained. Minor volume percentages ofthe compound in oxygen can often be employed. The amount used should besufficient to provide a significant anesthetic effect, but not so muchas to produce unacceptable deleterious side effects. Vaporconcentrations at which the compounds of this invention may often beused are about 1 to 4 volume percent, with the concentration actuallyemployed depending on the choice of anesthetic; for instance,2-chlorol,1,2-trifluoroethyl 2,2-difluoroethyl ether may often be usedin an amount of about 1 to 3%, 2,2- dichloro-l ,l-difluoroethyl2',2-difluoroethyl ether may often be used in an amount of about I to4%, and l,l,2,2-tetrafluoroethyl 2',2-difluoroethyl ether may often beused in an amount of about 2 to 4%. The amount of anesthesia to be usedcan be regulated, starting with a small amount of the ether andgradually increasing the amount until the desired plane of anesthesia isreached. By then monitoring the physical reactions of the mammal, as isthe usual procedure, the duration and plane of anesthesia can be readilycontrolled.

The ether compounds of this invention are also easily miscible withother organic liquids, including fats and oils, and have useful solventproperties, for example as solvents for fluorinated olefins and otherfluorinated materials, such as fluoro waxes. The compounds of thisinvention may be used to prepare pastes and dispersions of suchmaterials useful for coatings and the like, and may be used asdegreasing agents. In the latter capacity, for example, the ethercompounds of this invention can be used as solvents to remove grease orother oily substances from metal surfaces that are to be painted.

The following examples illustrate the preparation of the compounds ofthis invention.

EXAMPLE I This example illustrates the preparation of 2,2- difluoroethyl2'-chloro-l l ',2-trifluoroethyl ether.

Potassium hydroxide (6 g., 0.095 mole) was added to a solution ofcommercially obtained 2,2-difluoroethyl (i.e., CI-IF CH OH) (24.6 g.,0.3 mole) in dimethylsulf- EXAMPLE II This example illustrates thepreparation of 2,2- difluoroethyl l,l '-difluoro-2',2'-dichloroethylether.

The synthesis of CI-IF CH OCF CHCI was performed in the same manner asin Example 1, except that commercially obtained 1, l -dichloro-2,2difluoroethene (i.e., CF =CCl was used instead of CF =CFCL Calculatedfor C H CI F O C,22.33; H,l.86

Found C,22.60; H,l.66

This normally liquid material has a boiling point of 132C. and arefractive index (n,,) of 1.3721.

EXAMPLE III This example illustrates the preparation of 2,2-difluoroethyl 2'-hydroperfluoroethyl ether.

The synthesis of CHF CH OCF CF H was performed in the same manner as inExample I, except that commercially obtained perfluoroethane (i.e. CF=CF was used instead of CF =CFCI and the reaction was conducted in a 500cc. stirred autoclave at a pressure of 50200 psi.

Calculated for C.,I-I F O C,26.37; H,2.20

Found C,26.42; H,2.09

This normally liquid material has a boiling point of 775C. and arefractive index (n of l.29l3.

In order to determine the potency of the aliphatic ethers of the presentinvention as inhalation anesthetics in combination with oxygen, testswere carried out on mice. The compounds tested were at least 99.5% pureas determined by vapor phase chromatography. In the tests, the ethercompound is administered to test mice by a standard procedure in which ameasured quantity of the agent is placed in a laboratory jar and allowedto completely vaporize so as to give a calculated vapor concentration.The test mice are then quickly placed in the jar and observed.Anesthesia is determined by observing the righting reflex of the mice.Recovery time is measuredbeginning when the mice are transferred fromthe test jar to room air and ending when the mice are observed to beable to walk.

In such tests the 2-chloro-l,l,2-trifluoroethyl 2',2'- difluoroethylether induced anesthesia in the mice in 1 minute, 10 seconds when usedat a vapor concentration of 1.5 volume percent. Induction was smooth,but there was twitching throughout maintenance of the anesthesia.Recovery required 3 minutes, 40 seconds. When used at 2.5% vaporconcentration, essentially the same results were observed, except thatthe induction period was shortened to 50 seconds and the recovery periodwas lengthened to 5 minutes, 58 seconds. One mouse out of five wasbriefly cyanotic in the recovery period. At 3.5% concentration, theanesthesia was accompanied by undesired side effects, includingrespiratory depression to a rate of about per minute.

Use of 1.0% vapor concentration of the 2,2-dichlorol,l-difluoroethyl2,2'-difluoroethyl ether resulted in induction of anesthesia in 2minutes, seconds. The anesthesia was very light and the mice moved whileunder it. Recovery required 1 minute, 22 seconds.

The l,l,2,2-tetrafluoroethyl 2,2'-difluoroethyl ether, when used at 2.5%vapor concentration, barely induced anesthesia in 1 minute, 37 seconds.Recovery therefrom required 2 minutes and was accompanied byhyperexcitability. At 3.5% vapor concentration, the induction time was 1minute, seconds and the recovery time was 1 minute, 10 seconds. Therewas quivering during induction and, once again, hyperexcitability inrecovery. At 5.0 volume percent vapor concentration, the anesthesia wasaccompanied by undesirable side effects, including the deaths of 2 outof 5 mice treated.

While there have been decribed what are at present considered to bepreferred embodiments of the invention, it will be understood thatvarious modifications may be made therein which are within the truespirit and scope of the invention.

It is claimed: 1. An aliphatic ether compound of the formula CHF CH O CFCHX wherein each X is selected from the group consisting of F, Cl andmixtures thereof. I

2. The compound of claim 1 having the formula CHF CH O CF CHF 3. Thecompound of claim 1 having the formula CHF CH O CF CHFCI. 4. Thecompound of claim 1 having the formula CHF CH O CF CHCI UNITED STATESPATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,

DATED January 21, 1975 INVENTOR(S) I ROSS C. TERRELL It is certifiedthat error appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Col. 1, line 17, after "be" the word by should be inserted;

line 66, "difluoroethyl" should read difluoroethanol Signed and sealedthis 6th day of May 1975.

(SEAL) Attest:

C. MARSHALL DANN RUTH C. MASON Commissioner of Patents At-testingOfficer and Trademarks

2. The compound of claim 1 having the formula CHF2 - CH2 - O - CF2 -CHF2.
 3. The compound of claim 1 having the formula CHF2 - CH2 - O -CF2 - CHFCl.
 4. The compound of claim 1 having the formula CHF2 - CH2 -O - CF2 - CHCl2.